1. Field of the Invention
The present invention generally relates to methods and compositions for the eradication of cancers of the mucosal endothelial tissues. More particularly, the present invention relates to the use of such compositions and methods for breast cancer risk reduction, prevention and treatment.
2. Description of Related Art
For women with breast cancer, the term “eradication” has different meanings depending upon the state of their disease. Additionally, for women still disease free, eradication means preventing the development of breast cancer. Today, there are no known preventions for breast cancer. Although many risk factors have been identified for breast cancer (76-78), reduction of overall risk from the current United States level of one-in-eight has not been achieved short of the use of the anti-estrogen tamoxifen as a preventative (79). However tamoxifen is only for use by very high-risk women (79). It is not for use with the general population, both because of adverse side effects and because of disruption of reproductive capacity. Accordingly, tamoxifen is under evaluation for high-risk women, but is not considered appropriate for use as a standard preventative due to its serious side-effects and causation of a number of endocrine problems. Treatment with tamoxifen for more than five years may in fact induce breast cancer. It is now recommended that this therapy be limited to only five years. This does not cover the span of a women's lifetime. Based on knowledge today, it may be possible to reduce risk by alterations of life style and diet, but these are at best fractional gains and offer no assurances. Even women who lead very health-risk conscious lives still develop breast cancer. A successful mass prevention is a primary goal in the fight against this disease.
For women diagnosed with breast cancer, the current most effective eradication methods begin with various surgical procedures (i.e. mastectomy or breast conservation surgery or more commonly lumpectomy). Without doubt, removing a primary tumor is an effective first step of eradication provided tumor cells have not escaped to other body sites. Given that we understand that escape is a possibility, or that multiple unrecognized tumor foci are present in one or both breasts, many breast cancer patients opt for radiation therapy, adjuvant chemotherapy and/or tamoxifen treatment even when they are diagnosed as node negative. The term “node negative” indicates that cancer cells have not moved to the axillary nodes from the breast. Commonly however, it is thought useful to “shrink” primary tumors before surgical removal. Today this is done by systemic chemotherapy or radiation therapy. Patients with node negative estrogen receptor positive (ER+) breast cancer may also be treated with anti-estrogen (e.g. tamoxifen) as is often done for postmenopausal women. Depending upon age and physical condition, anti-estrogen therapy is now a common alternative for many postmenopausal women.
For breast cancer patients who are axillary node positive (either ER+ or ER−), additional treatment is essential including those noted above. There is no doubt that these modalities have a major positive impact on long term survival, but it is likewise clear to basic cancer investigators and cancer clinicians alike that the failure rate is significant even despite frequent quoting of favorable statistical data. Currently, node positive women without other evidence of dissemination can be treated by standard chemotherapy and/or radiation therapy. However, node positive patients with ER− tumors are at risk no matter the therapy utilized. For these women, the use of anti-hormone therapy is not as effective as with patients with ER+ tumors.
It is with the diagnosis of metastases to liver, bone, brain, lung, etc., that another more serious level of the eradication issues arises, and standard chemotherapy is most often not effective. For reasons both known and unknown, these cases have a very poor prognosis. Current chemotherapy can sometimes retard metastatic cancer growth, but as cancers spread they become progressively more therapy resistant. The level of public concern about this issue is clear from anticipation of the benefits of such new drugs as Herceptin®, which is a monoclonal antibody against the HER2 receptor. Introduction of Herceptin® was accompanied by widespread reports in the news media that heightened expectations. Unfortunately, even this new family of biopharmaceuticals is not an effective means of eradication. At best, Herceptin® provides only a small increase in survival time and then only in combination with chemotherapy and only with a minority of treated patients (70). While other types of drugs are under investigation, the magnitude of the disseminated cancer problem remains undiminished.
Iron deprivation has been discussed as a means of eliminating cancer cells (39,40), but the focus has been on two technologies that, used alone, have not worked. First, those investigators have considered iron deprivation via treatment with chelators that bind the metal and thereby render it metabolically inactive. Chelation alone has not removed enough iron from the body to be effective as an anticancer program (41). This is to be expected, for it is known that iron is retained in organs and tissues with a biological half-life of about 2000 days. Most likely, chelation alone will not be an effective therapy.
Currently, the primary effort in breast cancer research aimed at eradication of the disease is intensely focused by powerful technology that permits identification of a large number of genes, and by the human genome project that promises to solve the cancer problem. To date, these technologies have provided valuable information but have failed to move to the next level of application, cancer eradication.
A brief historical overview of breast cancer research over the past four decades points to numerous periods of advancement, each with its own promise of defeating cancer. For example, during the 1960s investigators were encouraged by newly identified enzyme and metabolic changes in cancer cells. It then seemed clear that these changes were the cause of cancer and that its end was near. During the 1970s, the beginnings of molecular biology (then called microbial genetics) yielded new found information that was thought certain to lead to the end of many human diseases, including cancer. Investigations in the field of endocrine cancer research, during the 1980s, focused on how hormones caused cell growth and developed animal models to study hormone dependent cancer. At that time, serum-free defined animal cell culture was being developed (1) and new substances called growth factors were being explored (2). Also during that period, another major advancement was the discovery of the estrogen receptor (ER) and the hypothesis that it alone controlled estrogen dependent cell growth (3-5). Some investigators did not accept all of the ER hypothesis (6-8), however, and thought that estrogen-inducible growth factors (estromedins) were necessary (6,9,10). It appeared clear at that time that growth factor research would untangle the cancer enigma. Today cancer scientists know this is not the case.
Along with the growth factor research came the “oncogene” explosion of the 1990s, which promised an end to cancer. Today, cancer investigators are inundated by scores of gene changes in cancer. The list grows weekly. A GENBANK search of “breast cancer hot spots” yielded more than 100 “hits” on several chromosomes. This cornucopia of genetic information obscures two facts: First, very few breast cancers can be traced to germ line DNA changes (11). Most are not inherited. Notable exceptions are BRCA1 and BRCA2, which represent at most 1-10% of breast cancers in the United States (31-33). Given that the incidence of breast cancer now approaches 1 in 8, the majority of breast cancers have other origins. Second, sophisticated new molecular technology has identified changes in expression of at least 100 mRNAs in breast cancer cells (11). There is promise of hundreds of gene/expression changes (11-13). It is very unlikely they are all causative or even critical to breast cancer. The tempting scenario is to investigate each mRNA or gene to define its role. Of course, this represents years of work for researchers, and still leaves open the question: “Will this lead to breast cancer eradication”?
It is known that eighty percent or more of breast cancers are invasive ductal carcinomas that arise from ductal cells (85,86) or precursors of ductal cells (85,87). Based on the current state of knowledge, there is no genetic lesion to explain the 70% of breast cancers now termed “sporadic”. Certainly the BRCA1 and BRCA2 genes are responsible for at most a small percentage of breast cancers in this country (88-91). Lesions in the p53 gene were initially thought to be important in as many as 15 to 50% of breast cancers (92-94). However, it was far from clear which mutations are causally related to breast cancer onset or which actually constitute secondary changes leading to loss of function of this tumor suppressor gene in the different types of breast cancer (i.e. ER+ or ER−). A more recent study has rightly pointed out the confusion regarding p53 mutations and breast cancer patients (96). Studies of p53 mutations have yielded a wide range of results depending upon the methods employed (97). One useful fact is that the results average about 30 to 40% for loss of heterozygosity at the p53 gene (97). This means the remaining gene may be a “hot spot” (i.e., a chromosomal loci or gene that is frequently altered in breast cancer specimens). However, at this time, there is not sufficient evidence to support the use of p53 as a guide to selection of therapy modalities for breast cancer (98).
In fact, today it is very difficult to explain the great many mutations and other types of genetic expression alterations that are known in breast cancer cells (11). Based on the findings with breast and other types of mucosal cancers, such changes include mutations, translocations, amplifications of oncogenes, loss of heterozygosity (LOH), and allelic imbalances (12,13,100-102). How do all of these happen? Are environmental carcinogens in such high abundance that they explain these data? Despite the concentrated focus given to environmental carcinogens as causes of breast cancer (20,95,99), that hypothesis has failed to move forward to the level of accepted scientific fact. Ways to reduce the risk of developing breast cancer, ways of preventing its occurrence, and ways to treat existing cases of localized and metastatic breast cancer are urgently needed. Even with the very best of treatments currently available, a longer-term plan is still needed in which prevention is the first line of eradication. A successful prevention will be, preferably, safe and have low or negligible side effects. It should be capable of reducing risk for the majority of women, independent of their economic circumstances. It should cause little or no disruption of life-style or reproductive capacity.